APOPTOSIS WITHIN SPONTANEOUSLY ACCEPTED MOUSE-LIVER ALLOGRAFTS - EVIDENCE FOR DELETION OF CYTOTOXIC T-CELLS AND IMPLICATIONS FOR TOLERANCE INDUCTION

MHC-mismatched liver grafts are accepted spontaneously between many mo use strains, The underlying mechanism(s) is unclear, In the B10 (H2(b) ) to C3H (H2(k)) strain combination used in this study, donor T cells within the liver were rapidly replaced within 2 to 4 days of transplan tation with those of the recipient, Freshly isolated liver graft-infil trating cells harvested on days 4 and 7 exhibited strong CTL responses against donor alloantigens. CTL activity was reduced substantially, h owever, by day 14, although levels of CTL precursors in the spleen and liver remained high, Examination of the liver allografts by in situ t erminal deoxynucleotidyltransferase-catalyzed dUTP-digoxigenin nick en d labeling on days 4, 7, and 14 after transplantation revealed promine nt apoptotic cells dispersed throughout the nonparenchymal cell popula tion, When acute liver allograft rejection was induced by administrati on of IL-2 from days 0 to 4 post-transplant (median survival time, 5 d ays), apoptotic activity (day 4) was reduced substantially, whereas CT L activity was enhanced, Nonparenchymal cells isolated from allografts of unmodified recipients 4, 7, and 14 days after transplantation exhi bited significantly higher DNA fragmentation after 18-h culture than c ells from liver isografts, Moreover, the level was 4 to 5 times higher than that of cells from IL-2-treated mice (on day 4), These observati ons suggest that T cell deletion, not regulation, may be responsible f or spontaneous liver allograft acceptance, The molecular recognition e vents that cause apoptosis of infiltrating T cells and why this occurs within liver grafts, but not heart or skin grafts, remain to be eluci dated.